The therapeutic advantage of an anticancer drug depends primarily on the extent to which the agent shows selective activity for tumour cells and the limiting toxicity towards non-target tissues. Frequently the poor quality of the vasculature within the growing tumour mass compromises the delivery of drugs, nutrients and oxygen. It is recognised that tumours can have significantly lower median oxygen levels (approximately 1% oxygen; pO2 7.5 mmHg) compared to normal tissues (˜5.5% oxygen; 42 mmHg) (summarised from data presented by Brown and Wilson, 2004). In addition, oxygenation levels can vary throughout the tumour due to intermittent opening and closing of tumour blood vessels; poor vascularisation, especially in the tumour core, contributes to oxygen levels often being below 0.1% oxygen (1 mm Hg). Tumour cells experiencing varying degrees of hypoxia, relative to normally perfused tissues, can compromise treatment effectiveness and contribute to the malignancy. Hypoxia-selective agents (e.g. bioreductive drugs) comprise one class of agents that can be used to target tumour cells in very low oxygen environments by virtue of a selective activation to a cytotoxic form under reduced oxygenation, addressing the problems of non-target tissue toxicity, hypoxic cell drug resistance and cancer progression.
Poor oxygenation results in a relative state of hypoxia when compared with normoxic conditions in which oxygenation has not been compromised. Poor oxygenation within tumours can modify the responses to treatment modalities and contribute to cancer progression. Cells in such hypoxic areas are particularly resistant to treatment with many of the conventionally used anticancer drugs; this is attributed to poor drug delivery and/or lack of intrinsic tumour cell sensitivity of viable but quiescent cells. Radiotherapy is also less effective at very low oxygen levels since the cytotoxicity of ionising radiation is enhanced by the presence of oxygen (Radiobiology For The Radiologist, Hall E J, Giaccia A J, Lippincott Williams & Wilkins, (2005)). Recent evidence shows that tumour cells can adapt to low oxygen conditions and change the pharmacodynamic responses to anticancer agents through the induction of active cellular protective mechanisms (Vaupel and Mayer 2007, Cancer Metastasis Rev 26(2): 225-239). Additionally, it is recognized that tumour cells that survive hypoxic stress often show a more malignant metastatic phenotype (Vaupel P, Metabolic microenvironment of tumor cells: a key factor in malignant progression, Exp Oncol 2010; 32, 125-127); this has significant consequences for the patient. Following treatment with modalities that target predominantly the better-oxygenated cells, the stress-resistant hypoxic cells often repopulate the tumour with cells that have an enhanced potential to spread to distant tissues. The development of more malignant metastatic tumours is often the precursor to a more significant disease-related morbidity and the death of the patient.
An attractive approach is the use of a hypoxia activated prodrug that is non-toxic towards adequately oxygenated cells found in systemic tissues, but becomes activated or converted to a cytotoxic form under reduced oxygenation conditions. N-oxide derivatives of cytotoxic alkylaminoanthraquinones provide anthraquinone pro-drugs that show almost no cytotoxicity. Importantly these prodrugs are capable of being converted in vivo under the anaerobic/hypoxic conditions found within neoplastic tissue. Specificity for the tumour is ensured since systemic tissues, except for tumours, almost never experience oxygen levels low enough to facilitate the production of the cytotoxic drug.
The anthraquinone N-oxide AQ4N (CAS#136470-65-0) is a prodrug that is selectively bioreduced to AQ4, a potent DNA topoisomerase II inhibitor, in hypoxic tumour cells. Previous publications have taught the fundamental properties and in-vitro/in-vivo characteristics of the prodrug AQ4N (for example, see U.S. Pat. No. 5,132,327).
The invention seeks to address the need for improved cancer treatments by providing novel anthraquinone compounds with a combination of preferable pharmacological and hypoxia-sensing properties.